System, method and apparatus with multiple reservoirs for in situ calibration of implantable sensors

ABSTRACT

A subcutaneous sensor system includes a sensor, a plurality of reservoirs, a plurality of pumps, a mixer provided with a plurality of mixer inlets and a mixer outlet, and a controller having an input coupled to the sensor output and a plurality of control outputs coupled to the plurality of pumps and the mixer. In certain embodiments, the system further includes an enclosure for the reservoirs, the pumps, the mixer and the controller, e.g. in the form of a skin patch or in the form of an implantable enclosure. In certain embodiments, the sensor is external to the enclosure and implanted beneath the skin tissue.

CROSS REFERENCE TO RELATED APPLICATION(S)

This application claims the benefit of U.S. Ser. No. 62/042,122, filedAug. 26, 2014, which is incorporated herein by reference.

BACKGROUND

Clinical chemistry enables the analysis of biological fluids fordiagnosing, monitoring, and/or treating the medical condition of apatient. By way of example, determining the level of analytes such asglucose, lactate, creatinine, electrolytes, and oxygen can be vitallyimportant for monitoring and/or maintaining a patient's health andtreatment. Moreover, a patient's reaction to the administration ofcertain substances (e.g. glucose) can be used in diagnosticstress-tests. Similarly, by monitoring the level of xenobiotics such asinsulin or drugs and their metabolites, physicians can diagnose kidneyand liver disorders or select appropriate dosing in drug treatment. Forexample, monitoring the pharmacokinetics of a drug under treatmentconditions in a particular patient can allow individualized optimizationof the treatment schedule and help avoid potentially serious drug-druginteractions.

Although centralized clinical laboratories can provide a wide array ofassays for accurately determining the presence and/or concentration ofvarious analytes, clinical laboratories typically require that a sample(e.g., blood) be obtained from a patient, shipped to a laboratory, andprocessed and tested prior to the results being communicated back to thepatient's physician. While recent advances in point-of-care (POC)diagnostics have enabled some laboratory tests to be quickly performedat the patient's bedside, these assays are not without drawbacks as theaccuracy and precision of POC instruments often suffer relative to theircentral lab counterparts.

By way of example, blood glucose has been the most frequently performedclinical chemistry laboratory test for the past several decades based,in part, on it serving as the primary indication for diabetes detectionand monitoring of therapy. Over the last years, however, self-testing ofblood glucose has become increasingly common with the advent of POCglucometers that allow an individual to lance their fingertip, expel adrop of blood onto a test strip that can be inserted into theglucometer, and obtain an almost immediate measurement of his or herblood glucose level.

Despite the frequency of sampling (e.g., at 15-, 30-, 60-, or 240-minuteintervals as specified by protocols), monitoring provided by glucometersand other analyte monitors is nonetheless discontinuous, providing asnapshot of analyte levels in the blood at the moment that the samplewas obtained. Accordingly, systems have been developed to continuouslymeasure the concentration of analytes in subcutaneous interstitialfluid, for example, since the concentration of certain analytes (e.g.,glucose) is highly correlated between these two fluid compartments(Bantle, et al., J. Lab. Clin. Med. 1997; 130: 436-441), incorporatedherein by reference. By way of example, sensors for continuousmonitoring of certain analytes (e.g., glucose) in interstitial fluid areknown in the art. U.S. Pat. No. 6,579,690 of Bonnecaze et al. and U.S.Application Pub. No. 2008/0027296 of Hadvary et al., both of which areincorporated herein by reference, provide continuous analyte monitoringsystems that may enable better glycemic control through continuous,real-time monitoring of a patient's interstitial fluid glucose levels.Some such systems, for example, employ an electrochemical sensor thatcan be implanted within subcutaneous tissue and remain in contact withthe interstitial fluid for an extended time (e.g. several hours to aweek or more). The voltage output of the sensor can be transmitted to adata processing unit (e.g. a microprocessor, a microcontroller, etc.)for converting the sensor output to a blood glucose equivalent value.

Like POC glucometers and other POC analyte measurement systems,implantable analyte monitoring systems can suffer from diminishedaccuracy and precision relative to their clinical laboratorycounterparts. Moreover, the long-term implantation of these monitors candiminish the reliability of the data transmitted by the sensor(s) asother components in body fluids (e. g., proteins) can contaminate thesensors and cause inaccurate readings. As a result, current continuousanalyte monitoring systems generally require frequent calibration orconfirmation using other more invasive and/or less convenienttechniques. By way of example, prior to treating a patient in whom theircontinuous blood glucose monitor indicates a low blood glucose level, amedical caretaker is generally required to confirm the levels using thestandard-of-care POC glucometers. Likewise, diabetics using implantable,continuous glucose monitors are nonetheless prompted to provide a fingerstick measurement for regular calibration of their monitors and/or priorto treatment. Accordingly, there remains a need for improved accuracyand reliability of implantable, continuous analyte monitoring systems,such as the continuous glucose monitor (CGM).

A CGM typically takes the form of a patch which is applied to the skinor implanted under the skin. Typically, the electrochemical sensorassociated with the CGM patch is either implanted or inserted inside thehuman body and is therefore subject to a “foreign body response” wherethe body tries to render the sensor inert. This response changes theperformance of the sensor as well as aging of the sensor may also changethe performance. It is therefore desirable to have an in situ method forrecalibrating sensors as their performance changes with time.

Systems, devices and methods for in situ calibration of implantablesensors are described in International Application No. PCT/US2012/070025of Winkelman (published as WO 2013/090882 A1) incorporated herein byreference. In one aspect, Winkelman describes a system for monitoringthe concentration of an analyte including a sensor configured to beimplanted at an implant site in a patient's skin, the sensor configuredto sense an analyte present in a biological fluid at the implant site.The described system can additionally include a reservoir, whichcontains a calibration fluid having a known concentration of theanalyte, and a conduit for delivering the calibration fluid from thereservoir to the implant site, to allow for the calibration of thesystem.

While Winkelman provides the advantage of being an in situ calibrationsolution, it is limited by its single-point calibration methodology.With Winkelman, a “calibration fluid”, e.g. a control solution of aknown value such as 100 mg/dL, is pumped from a reservoir into theinterstitial tissue proximate to the sensor. The known value may be farfrom the value that the sensor was measuring, potentially causing asignificant calibration error. Also, Winkelman only measures at a singlepoint, such that both the gain and offset of the transfer function forthe linear range of the sensor may be skewed. Still further, the methoddisclosed by Winkelman is limited in application due to the use of asingle, fixed reservoir of calibration fluid.

These and other limitations of the prior art will become apparent tothose of skill in the art upon a reading of the following descriptionsand a study of the several figures of the drawing.

SUMMARY

In non-limiting examples, systems and processes are provided tocalibrate an in situ electrochemical sensor with a control(“calibration”) solution that can be programmed to continuous values inthe range of the sensor's linear measurement range. The systems andprocesses are described with reference to example continuous glucosemonitors but can also be used for an electrochemical sensor measuringchemicals other than glucose in interstitial fluid or blood. The exampleprogrammable control solution can provide a single point calibrationthat can quickly return to measuring glucose and/or can provide a twopoint calibration resulting in a more accurate glucose reading comparedto a single point calibration. Furthermore, the example systems andprocesses described herein can provide a safety check on the sensoroperation, or perform a cleaning of the sensor, to ensure properoperation.

In an embodiment, set forth by way of example but not limitation, asubcutaneous sensor system or device with multiple reservoirs forcalibrating solutions includes a sensor having a sensor output; aplurality of reservoirs provided with a corresponding plurality ofreservoir outlets; a plurality of pumps provided with a correspondingplurality of pump inlets and a corresponding plurality of pump outlets,wherein the plurality of pump inlets are coupled to the plurality ofreservoir outlets; a mixer provided with a plurality of mixer inlets anda mixer outlet, wherein the plurality of mixer inlets are coupled to theplurality of pump outlets; and a controller having an input coupled tothe sensor output and a plurality of control outputs coupled to theplurality of pumps and the mixer. In certain embodiments, the systemfurther includes an enclosure for the reservoirs, the pumps, the mixerand the controller, e.g. in the form of s skin patch or in the form ofan implantable enclosure. In certain embodiments, the sensor is externalto the enclosure and implanted beneath the skin tissue.

In certain non-limiting examples the controller includes amicrocontroller unit (MCU) including digital memory, a sensor analogfront end (AFE) coupling the MCU to the sensor with a conductor at leastpartially enclosed within a tube connected to the mixer output, a datainterface coupled to the MCU, and an auto-calculation (Autocal)controller coupling the MCU to the plurality of pumps and to the mixer.

In certain example embodiments, the system is provided with a pluralityof reservoirs filled with control (“calibration”) solutions of differentvalues. For example, the system can include a first reservoir of theplurality of reservoirs contains a first calibration solution and asecond reservoir of the plurality of reservoirs contains a secondcalibration solution different from the first calibration solution. Forexample, the first calibration solution is chosen to be proximate afirst end of a linear operating region of the sensor and the secondcalibration solution is chosen to be proximate a second end of thelinear operating region of the sensor. In certain example embodiments,the first calibration solution and the second calibration solution canbe mixed in the mixer to provide a third calibration solution that isintermediate to the first calibration solution and the secondcalibration solution. In other example embodiments, the system includesa third reservoir for a cleaning solution. In certain embodiments, themixer includes one or more mixing valves, and the controller is, in partor in whole, provided as an integrated circuit.

In an embodiment, set forth by way of example and not limitation, amethod for operating a subcutaneous sensor system with multiplereservoirs for calibrating solutions includes: (a) detecting thepresence of calibration-triggering event with a microcontroller; (b)measuring an initial value of the interstitial tissue of a patient witha subcutaneous sensor; (c) bathing the sensor with a first calibrationsolution having a different value than the initial value, the firstcalibration solution being provided from at least one of a plurality ofreservoirs; (d) measuring a first calibration value from the sensor thatis associated with the first calibration solution; (e) bathing thesensor with a second calibration solution having about the same value asthe initial value, the second calibration solution being provided by atleast one of the plurality of reservoirs; (f) calculating the gain (m)and offset (b) for the sensor, whereby the transfer function f(x) forthe sensor comprises y=f(x)=mx+b; and (g) using the transfer function tomeasure a calibrated sensor value of the sensor. In the case of a CGM,the initial value can be for example, the initial glucose value of theinterstitial fluid of a patient.

An advantage of certain example embodiments is that the need fordiabetics to perform finger stick blood glucose measurements multipletimes daily to calibrate their CGM patches is eliminated.

A further advantage of certain example embodiments is that a CGM canreturn to measuring glucose in the interstitial fluid faster than in theprior art after performing a single point (offset) calibration.

A still further advantage of certain example embodiments is that amulti-point measurement can be made to perform a two-point (gain andoffset) calibration.

Another advantage of certain example embodiments is that a safety checkof the sensor's operation can be performed.

Yet another advantage of certain example embodiments is that a cleaningof the sensor can be accomplished with a specialized cleaning fluid.

These and other embodiments, features and advantages will becomeapparent to those of skill in the art upon a reading of the followingdescriptions and a study of the several figures of the drawing.

BRIEF DESCRIPTION OF THE DRAWINGS

Several example embodiments will now be described with reference to thedrawings, wherein like components are provided with like referencenumerals. The example embodiments are intended to illustrate, but not tolimit, the invention. The drawings include the following figures:

FIG. 1 is a block diagram, set forth by way of example and notlimitation, of a subcutaneous sensor system with multiple reservoirs forcalibrating solutions;

FIG. 2 is a block diagram, set forth by way of example and notlimitation, of a subcutaneous sensor system with two reservoirs suitablefor use as a continuous glucose monitor (CGM);

FIG. 3 is a block diagram, set forth by way of example and notlimitation, of a microcontroller unit (MCU) of FIG. 2;

FIG. 4 is a block diagram, set forth by way of example and notlimitation, of a sensor analog front end (AFE) for the subcutaneoussensor system of FIG. 2;

FIG. 5 is a block diagram, set forth by way of example and notlimitation, of another sensor analog front end (AFE) for thesubcutaneous sensor system of FIG. 2;

FIG. 6 is a flow diagram, set forth by way of example and notlimitation, of an example process stored as code segments in memory andexecuting on the processor of the microcontroller unit (MCU) of FIG. 3;and

FIG. 7 is a flow diagram, set forth by way of example and notlimitation, of an example Process Calibrate Event process of FIG. 6.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

FIG. 1 is a block diagram, set forth by way of example and notlimitation, of a subcutaneous sensor system 10 with a plurality ofreservoirs 12 for solutions. Sensor system 10 also includes a pluralityof pumps 14, a mixer 16, a controller 18 and a subcutaneous sensor 20.In this non-limiting example, there are N reservoirs 12, at least two ofwhich include calibrating solutions of different values. In anembodiment, at least one of the reservoirs includes a cleaning solution.In this non-limiting example, there are N pumps 14 (labelled P1-PN) tocouple N inlets of mixer 16 to N outlets of reservoirs 12. The pumpsP1-PN are controlled by control lines C_(P1)-C_(PN) coupled to outputsof the controller 18. Mixer 16 is controlled by control line C_(M)coupled to an output of the controller. It should be noted that mixer 16can be a single mixing valve or a plurality of mixing valves. Sensor 20is coupled to an input of controller 18.

FIG. 2 is a block diagram, set forth by way of example and notlimitation, of a subcutaneous sensor system 22 with two reservoirs 24suitable for use as a continuous glucose monitor (CGM). In thisnon-limiting example, two pumps 26 couple outlets of the reservoirs 24to a mixing valve 28. Also in this example embodiment, controllercomponents are distributed among a microcontroller unit 30, anAuto-calibration (Autocal) Control 32, a sensor analog front end (SensorAFE) 34 and Data Interface 36. A subcutaneous sensor 38 is coupled to aninput of the Sensor AFE by a conductor 40 which, in this non-limitingexample, is at least partially disposed within a tube 42 coupled to anoutlet of mixing valve 28.

In this non-limiting example, the reservoirs 24, pumps 26, mixing valve28 MCU 30, Autocal Control 32, Sensor AFE 34 and Data Interface 36 aredisposed within an enclosure 44. In one example embodiment, theenclosure 44 is a skin patch which sits on top of skin tissue 46, and inanother example embodiment the enclosure is implanted within the body soas to be beneath skin tissue 46′. The tube 42, conductor 40 and sensor38 extend from the enclosure into the body of a patient.

FIG. 3 is a block diagram, set forth by way of example and notlimitation, of a microcontroller unit (MCU) 30 of FIG. 2. The MCU 30, inthis non-limiting example, includes a microprocessor unit (MPU) 48,flash memory 50, electrically programmable read-only memory (EPROM) 52,random access memory (RAM) 58, and input/output (I/O) ports 56, 58 and60. Collectively, flash memory 50, EPROM 52 and RAM 54 comprise digitalmemory 55 (a/k/a non-transitory computer readable media) that can beaccessed by MPU 48. In this non-limiting example, I/O 56, 58 and 60couple Data Interface 36, Autocal Control 32 and Sensor AFE 34,respectively, to MPU 48.

FIG. 4 is a block diagram, set forth by way of example and notlimitation, of a first sensor analog front end (AFE) 34′ for asubcutaneous sensor 38′. In this non-limiting example, AFE 34′ includesa digital-to-analog converter (DAC) 62, an operational amplifier 64, adifferential programmable gain amplifier (PGA) 66, and ananalog-to-digital converter (ADC) 68. The AFE 34′ also includes areference voltage generator 70 producing a reference voltage REFADC forthe ADC and a reference voltage REFDAC for the DAC. A negative feedbacknetwork comprising a capacitor 72 and resistor 74 is provided foroperational amplifier 64, and switches 76 and 78 selectively eitherengage or bypass the PGA 66. A single-pole double-throw (SPDT) switch 80selectively couples either REFADC or REFDAC to the reference input ofADC 68. Sensor 38′ is coupled between the negative input to operationalamplifier 64 and ground. In this non-limiting example, sensor 38′ is atwo-terminal, self-biased electrochemical sensor.

FIG. 5 is a block diagram, set forth by way of example and notlimitation, of a second sensor analog front end (AFE) 34″ for thesubcutaneous sensor 38″. AFE 34″ is substantially similar to AFE 34′,where like reference numbers refer to like components, but with theaddition of a DAC 82 and an operational amplifier 84 coupled to sensor38″. In this non-limiting example, sensor 38″ is a three-terminal,counter configuration electrochemical sensor.

FIG. 6 is a flow diagram, set forth by way of example and notlimitation, of an example process 86, which can be stored as codesegments in memory 55 to be executed by MCU 48 of FIG. 3. Process 86begins, typically upon power-up, at 88 and, in an operation, the systeminitializes. Next, in an event loop 92, various inputs such as a timer94, I/O 96 and Other 98 are monitored for events (which can be in theform of interrupts to the MCU 48). If there are no events to process,the event loop 92 continues to idle as indicated at 100.

If an I/O event is detected by event loop 92 it is processed byoperation 102, after which time process control returns to the eventloop 92. Similarly, clean events, calibrate events, and measurementevents are processed by operations 104, 106 and 108, respectively.Several of the events can be triggered by a timer input 94. For example,measurements events can be processed by operation 108 on a regular,timed basis. Calibrate events can similarly be performed on a regularbasis, or just after startup. I/O events may be externally triggered byan operator, and clean events may be initiated when the system fails toproperly calibrate. Other events and triggers, as well as otherevent-driven processes, will be apparent to those of skill in the art.

FIG. 7 is a flow diagram, set forth by way of example and notlimitation, of an example Process Calibrate Event process 106 of FIG. 6.This example process, which is described with reference to themonitoring of glucose levels in, for example, a continuous glucosemonitor (CGM), begins at 112 and, in an operation 114, the currentglucose value is measured in an operation 114. Next, it is determined ifthe glucose value is less than 250 mg/dL. If so, the sensor is bathed ina 500 mg/dL calibration solution from one of the reservoirs. If not, thesensor is bathed in a 50 mg/dL calibration solution from another one ofthe reservoirs. Next, in an operation 122, the sensor current ismeasured and stored along with the selected calibration solution value.In an operation 124, the sensor is then bathed in a mixed calibrationsolution derived from the two reservoirs at the measures glucose valueof operation 114. Operation 126 uses the stored current measurements andthe calibration values to calculate gain (m) and offset (b) for thetransfer function f(x) for the linear range of the sensor as given by:

y=f(x)=mx+b  Equation 1

The transfer function can then be used to transform the electricalcurrent value “x” measured by the sensor to calibrated glucose values“y” in an operation 128. The process 106 is then completed at 130.

It will be appreciated that, in the example embodiments set forth above,that a calibration solution can be programmed over a range of 50 to 500mg/dL depending on what value the sensor is reading and desired actionto be taken. During a single point calibration, the control solution canbathe the sensor with the value that the sensor is currently measuringso that the sensor doesn't deviate significantly from its current value.In general, the time constant on these sensors is large, so if they arecalibrated close to the current value the time to return to measuringglucose in the interstitial fluid will be significantly faster. Also, incertain example embodiments, a two-point calibration can be performedbecause of the ability to program the calibration solution such that itcan sequentially bathe the sensor at a first value such as 50 mg/dL, andthen in a second value closer to the measured value, such as 200 mg/dL.This results in transfer function calibration that provides moreaccurate glucose measurements in the interstitial fluid. Also, exampleembodiments can perform a safety check on the sensor operation byintentionally bathing the sensor with a control solution that isintentionally far from the current value to see how the sensor respondsto this change in glucose, or the sensor can be bathed in a cleaningsolution provided by an additional reservoir.

The apparatus block diagram in FIG. 2 illustrates the system componentsfor the example of a CGM. More particularly, Reservoir 1 and Reservoir2, of this non-limiting example, contain a control solution used tocalibrate the sensor 38. One reservoir has a control solution at the lowend of the linear measurement range, such as 50 mg/dL, and the otherreservoir has a control solution at the high end of the linearmeasurement range, such as 500 mg/dL. Pump 1 and Pump 2 pump aprogrammable volume of control solution from each reservoir to be mixedin mixing valve 28 to create a control (“calibration”) solution in orderto calibrate any desired value within the measurement range. The Autocalcontrol block can include electronics to control the creation anddelivery of the mixed calibration solution.

With continuing reference to FIG. 2, the sensor is used to measureglucose in the interstitial or other biological fluids. It can be housedin a cannula or similar tube like structure 42 in order to delivercalibrant to the sensor in situ. The sensor AFE 34 includes electronicsto interface to the sensor and can provide bias or stimulus and measureelectrical changes in the sensor. The MCU 30 has digital electronics torun the system program and control the overall operation of the system.The Data Interface includes electronics to facilitate the sending andreceiving of data between this system and a remote device, and can beeither a wired or wireless interface.

In operation, on a periodic basis an automatic calibration sequence willbe initiated to perform one or more of the following operations:

-   Measure the glucose value in the interstitial fluid by measuring the    current from the sensor and calculating the glucose value using the    most recent calibrated transfer function;-   If glucose value is less than 250 mg/dL, bathe the sensor in a high    value control solution such as 500 mg/dL. If the glucose value is    250 mg/dL or greater, bathe the sensor in a low value control    solution such as 50 mg/dL. After waiting for the sensor to respond,    measure the current from the sensor and note associated calibrant    value;-   Program the control solution or calibrant to be the measured glucose    value and bathe the sensor with the solution. After waiting for the    sensor to respond, measure the current from the sensor and note    associated calibrant value;-   Use the known calibrant values and measured currents to calculate    the gain and offset in the form of y=mx+b where m is the gain and b    is the offset, and store the result; and-   Wait for the sensor to rid itself of the calibrant and where it is    bathed in the interstitial fluid. Measure the glucose value in the    interstitial fluid by measuring the current from the sensor and    calculating the glucose using the most recent calibrated transfer    function. This calibration sequence serves the purpose of performing    a two point calibration, which is more accurate than a single point    calibration, and it serves as a check on the sensor operation by    using a calibrant value far from the current value as the first    point, and returns the sensor to normal.

Although various embodiments have been described using specific termsand devices, such description is for illustrative purposes only. Thewords used are words of description rather than of limitation. It is tobe understood that changes and variations may be made by those ofordinary skill in the art without departing from the spirit or the scopeof various inventions supported by the written disclosure and thedrawings. In addition, it should be understood that aspects of variousother embodiments may be interchanged either in whole or in part. It istherefore intended that the claims be interpreted in accordance with thetrue spirit and scope of the invention without limitation or estoppel.

What is claimed is:
 1. A subcutaneous sensor system with multiple reservoirs for calibrating solutions comprising: a sensor having a sensor output; a plurality of reservoirs provided with a corresponding plurality of reservoir outlets; a plurality of pumps provided with a corresponding plurality of pump inlets and a corresponding plurality of pump outlets, wherein the plurality of pump inlets are coupled to the plurality of reservoir outlets; a mixer provided with a plurality of mixer inlets and a mixer outlet, wherein the plurality of mixer inlets are coupled to the plurality of pump outlets; and a controller having an input coupled to the sensor output and a plurality of control outputs coupled to the plurality of pumps and the mixer.
 2. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 1 further comprising an enclosure for the reservoirs, the pumps, the mixer and the controller.
 3. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 2 wherein the enclosure comprises a skin patch.
 4. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 2 wherein the enclosure is implanted beneath skin tissue.
 5. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 2 wherein the sensor is external to the enclosure and is implanted beneath skin tissue.
 6. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 1 wherein the controller comprises a microcontroller unit (MCU).
 7. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 6 wherein the MCU includes digital memory.
 8. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 6 wherein the controller further comprises a sensor analog front end (AFE) coupling the MCU to the sensor.
 9. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 8 wherein the sensor is coupled to the AFE with a conductor.
 10. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 9 wherein the conductor is at least partially enclosed within a tube connected to the mixer outlet.
 11. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 6 wherein the controller further includes a data interface coupled to the MCU.
 12. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 6 wherein the controller further includes an auto-calculation (Autocal) controller coupling the MCU to the plurality of pumps and to the mixer.
 13. A subcutaneous sensor system with multiple reservoirs for calibration solutions as recited in claim 1 wherein a first reservoir of the plurality of reservoirs contains a first calibration solution and a second reservoir of the plurality of reservoirs contains a second calibration solution different from the first calibration solution.
 14. A subcutaneous sensor system with multiple reservoirs for calibration solutions as recited in claim 13 wherein the first calibration solution is chosen to be proximate a first end of a linear operating region of the sensor and the second calibration solution is chosen to be proximate a second end of the linear operating region of the sensor.
 15. A subcutaneous sensor system with multiple reservoirs for calibration solutions as recited in claim 14 wherein the first calibration solution and the second calibration solution can be mixed in the mixer to provide a third calibration solution that is intermediate to the first calibration solution and the second calibration solution.
 16. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 13 further comprising a third reservoir for a cleaning solution.
 17. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 1 wherein the mixer comprises a mixing valve.
 18. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 17 wherein the mixer comprises a plurality of mixing valves.
 19. A subcutaneous sensor system with multiple reservoirs for calibrating solutions as recited in claim 1 wherein the controller comprises an integrated circuit.
 20. A method for operating a subcutaneous sensor system with multiple reservoirs for calibrating solutions comprising: detecting the presence of calibration-triggering event with a microcontroller; measuring an initial value from a subcutaneous sensor; bathing the sensor with a first calibration solution having a different value than the initial value, the first calibration solution being provided from at least one of a plurality of reservoirs; measuring a first calibration value from the sensor that is associated with the first calibration solution; bathing the sensor with a second calibration solution having about the same value as the initial value, the second calibration solution being provided by at least one of the plurality of reservoirs; calculating the gain (m) and offset (b) for the sensor, whereby the transfer function f(x) for the sensor comprises y=f(x)=mx+b; and using the transfer function to measure a calibrated sensor value of the sensor. 